Frequently Asked Questions about Dr. Cheng and his Lab's work

What is your goal in life?

My personal goal is to make a maximum contribution to society.

Pigmentation Research

What might your work in human pigmentation contribute to human health?

Since the gene is highly expressed in all pigment cells, the new gene adds one more tool for research into potential modes of immunotherapy against malignant melanoma. It also adds one more tool for researchers seeking ways to allow lighter-skinned people to darken their skin more safely than currently done now on the beach or tanning salons, which involves cancer-causing UV light.

What do you hope the pigment gene discovery might contribute to society?

It is truly remarkable that one of the most notable differences between branches of humanity, skin color, has on the one hand been the basis of terrible injustice, and on the other hand, been due to a change in one base pair out of the three billion in the human genome. Many of us in genetics hope that this finding will begin to demystify race, which is a complex of physical features dictated by genetics, and sociological features (language, culture, clothes, religion) that have nothing to do with genetics. I believe a positive evolution of society will include a more precise and clear understanding of the contribution of differences to the richness of mankind. I also hope that people become more aware of the times when our human frailties, greed and insecurity, mislead us to claim superiority as a result of differences. For those of you fortunate enough to have escaped the horror and loneliness of racism, please read the sermon given by my colleague John Pawelek (Yale U.) on Sunday, January 22, in honor of Martin Luther King.

What have been the most common public misconceptions about skin color?

Among the most frequent misconceptions are that SLC24A5 is “the” gene for skin color and that genes are present or absent in different ethnic groups.

Our work shows that a single-letter variation in the entire genome, in the SLC24A5 gene, causes the most prominent, common difference in skin color between the races, that between Europeans and Africans. The evidence suggests the possibility that greater activity for this gene is associated with a greater number, size and density of the melanosome. The fact that what seems to be a “dead” form of this gene still allows for the formation of pigmentation in the zebrafish suggests that this gene is a modulator, not an “on-off” switch for the formation of melanosomes.

Many genes contribute to skin color. Variation in these genes determines skin color. We know that many genes contribute to skin color for two reasons. First, there is great variation in skin color in all races. You cannot achieve great variation without many contributors. The second reason we know there are many genes is that decades of scientific work with human, mouse and other organisms have identified variations in over 100 genes that affect skin color. We know that pigmentation involves a number of cellular components and processes. These include enzymes involved in the stepwise synthesis of different types of melanin pigment, modulation of the number, size and density of the pigment-containing cell packages (the melanosome), transfer of melanosomes out of the pigment cell (the melanocytes) into the main cell type making up our skin (the keratinocyte), and the genetic controls over how much and how rapidly we are able to adapt our color to the amount of sun we are exposed to. There exist single letter differences, in many, and perhaps all of these proteins. Some of these variations may contribute to different levels of pigmentation. In our case, we have found a single letter spelling difference in one gene that plays an important, but not well-understood role in modulating the formation of the melanosome. In sum, SLC24A5 is not “the” gene for skin color.

Will it be at all possible to change a person’s skin color from white to black or black to white in the near future? Or do you think your discovery can allow people to have a choice in what skin tone they have?

It seems likely, on the basis of our increasing understanding of pigmentation, that it will be possible to find ways to make our skin lighter or darker. At the same time, it is worth pausing to consider the need for and value of changing our skin color. Should self-worth be determined by how we look, or by something else? Might it be better to culture our ability to perceive the beauty inherent in variation, contrast and diversity, and to focus our energy and resources instead on making the world a better place for all?

Does the work on SLC24A5 bring us closer to a cure for vitiligo?

Vitiligo is a disease of unknown origin that causes patches of depigmentation in 1-2% of the world population, regardless of race. Unfortunately, since the mechanism of this disease appears to be autoimmune in origin, I see no direct way to use our identification of a new pigment gene to solve this difficult problem. This does not mean that others will not. To learn more about vitiligo, see http://www.nvfi.org/, http://www.skinsite.com/info_vitiligo.htm, and http://www.niams.nih.gov/hi/topics/vitiligo/vitiligo.htm. I have heard from a number of people with vitiligo who are seeking a cure. Since I am currently powerless, all I can do is to encourage them to remember that we cannot control how other people act, but we can change how we respond. Similarly, I have noticed that we pretty much decide whether or not we are happy, regardless of circumstance. There's always someone worse off than us.

I heard that you met with the Race, Ethnicity, and Genetics Working Group at the National Human Genome Research Institute at NIH. What were your conclusions?

We agreed that race is a term of very limited scientific value, since we now know that there is more genetic variation within populations (commonly referred to as "races") than between them. However, we also agreed that, in dealing with the public, which uses the term, seeming to be evasive about it may be loosing an opportunity to demystify it and to clarify its use in discussion. Race, as a descriptor of populations, has two basic components. The first deals with physical features, perhaps most prominently skin color, and also including facial features and other bodily characteristics. These are genetic. The second deals with sociological issues that are clearly not genetic, including culture, language, country, and religion. While there are varying probabilities of having specific physical features associated with sociological groups, the links are not fixed. We also agreed that it is important to establish, at the beginning of every discussion about race, whether the discussion is aimed at putting down one group in favor of one's own, which is destructive in purpose and based on human frailties such as insecurity, or whether it is aimed at understanding and celebrating the rich diversity of life, which is constructive in purpose.

Tell us more about mutation and evolution.

Mutation is change in the base composition of a genome, including single base changes (single letters of our instruction book of life), small or large insertions of deletions, sometimes involving regions of the genome as large as entire chromosomes. Interestingly, the scientist places no particular value on mutation. "Value" of a mutation simply depends upon the environment. Just like many personality traits or features of life, it whether something is "good" or "bad" depends upon the situation. Darwin's finches with different beak shapes were suited to their specific environments, and not to others. Some of the mutations that made it possible for people to survive in periods of starvation are today associated with diabetes and high blood pressure. In the case of skin color, dark color was necessary for survival in the area of the world that was less affected by the ice ages – equatorial Africa, where sun stroke, blistering, and skin cancer would result from lighter skin. On the other hand, dark skin reduces survival in areas of little sun. It is well-known that dark-skinned individuals are much more likely to suffer from rickets in more northern latitudes than light-skinned individuals. (Indeed, it is fun to consider the possibility that the availability of Vitamin D milk tens of thousands of years ago may have resulted in us being all brown-skinned!) Thus, in order for man to be able to survive in northern latitudes of diminished sunlight, it was critical to evolve lighter skin colors that would still allow enough UV light through the skin to produce vitamin D.

As every student of science knows, mutations are a fact. Mutations occur spontaneously from the normal chemical instability of DNA, from characteristic levels of inaccuracy of the cellular machinery that handles our DNA, and from normally-present mutagenic substrates for DNA and mutagenic influences of our environment (such as sunlight). These mechanisms have been my career interest (see the Cheng and Loeb paper above).

Mutations provide the fuel for evolution. Evolution, through mutation, provides a plausible scientific mechanism for the diversity of us as individuals, and the diversity of organisms. Geneticists watch evolution occur every day in their laboratories, whether in the form of new combinations of genes (recombinants) during mitosis or meiosis, spontaneous mutations that make bacteria resistant to viruses or fish strains with different patterns of pigmentation arise. Physicians see the results of evolution every day in patients in which bacteria become resistant to antibiotics, or cancers become resistant to chemotherapy. Unfortunately, that evolution will be accelerated in the presence of mutagenic chemical or physical agents. Many examples of mutagenic chemicals are present in cigarette smoke (it greatly increases your risk of lung cancer). The most commonly known examples of mutagenic physical agents is UV light (from the sun or Tanning salons). Note that an evolution from a normal cell to the multiple harmful features of most cancers is responsible for every cancer that will kill about one in very three people in the U.S. Many geneticists, like me, are interested in knowing more about these mechanisms of mutation. I hope that obtaining a greater understanding of mutation and its role in the evolution of cancer will yield new ways to treat cancer.

Is there any direct evidence that SLC24A5 is related to intelligence?

No. Expression of SLC24A5 in the brain has been increasingly, incorrectly cited as evidence of a role for this gene in intelligence. Since thousands of genes are expressed in each tissue, it is just as correct to ascribe a role of one expressed gene in the brain to in intelligence as it is to claim that racing car seats are the responsible mechanism for making cars fast – after all, are not race car seats very frequently found in racing cars? It is similarly incorrect to cite car seats as the mechanism for fast cars on the basis of their frequency in the "Westernized" regions. The properly-trained geneticist will do the correct experiment with these cars – mutate the car seat alone in different cars – non-race car seat to a racing car seat, or vice versa, and see what happens to the speed of the car.

In the area of pigmentation, we know of many examples of mutations that cause albinism. Just because mutations in a gene cause albinism does not make those genes key in the evolution of significant differences in skin pigmentation between human populations. The same goes for intelligence genes. Unbiased, carefully-controlled functional evidence would be required to justify such assertions. It is furthermore worth asking what motivation drives such inquiry.

Is there anything not talked about with regard to the skin pigmentation work you would like to point out?

Yes. It is a time to celebrate and to be thankful. The HapMap project, which made much of the later work possible, involved legions of scientists in many countries, dedicated to the goal of putting up a free web-based catalogue of specific differences in the human genome, in the hope of some day providing greater understanding, and curing human disease. There are few achievements in all of human history that match this. Second, there are many heroes in this work, including all the trainees and collaborators who worked long and hard on this project in many different ways, and applied their intelligence to solving a common set of problems. Without this collaborative effort, this finding would not have been possible. The work has been graced by the unselfish and helpful attitudes of some extraordinary people. A partial list: Charline Walker, generously and patiently introduced me to many details of the zebrafish in the early 90's. David Grunwald graciously offered reagents and ideas without ever expecting anything back. Nancy Mangini patiently and excitedly offered the core components of the model shown in Figure 4E. Victor Canfield applied uncompromising integrity to the drawing of scientific conclusions. Becky Lamason showed extraordinary maturity and diligence in the face of challenge and transitions. Many of my co-authors and advice-givers showed great patience with my frequent and challenging questions. Others, including Mark Shriver, Mark Kittles, and Francis Collins offered kind advice when I was concerned about the issue of race.

When did you become interested in genomic instability?

One of the specific phenotypes of cancer I was intrigued by as a medical student was the frequent finding of atypical mitoses. I wondered how they occurred and what role they might play in cancer. As a graduate student studying recombination in lambda phage in the laboratory of Gerald Smith at the “Fred Hutchinson Cancer Research Institute” in Seattle, I used mismatch correction deficient mutants to preserve heteroduplexes I predicted would exist in specific places during recombination that is stimulated by Chi hotspots. In 1985, as I was thinking about the potential role of mismatch correction in cancer, I realized for myself that a mutator phenotype, from any mechanism, could play an important role in cancer. The basis of this idea had been elegantly described by Peter Nowell in 1976. This interest led me to the lab of the primary proponent of this idea, Larry Loeb (University of Washington), for my postdoctoral training.

When did you decide to use zebrafish as a cancer model?

At the end of my postdoc, in 1991, as I was trying to determine how I might make my contribution to science, I decided to search for a genetic model for genomic instability in which I could do a mutator screen and in which cancer could be studied. I hypothesized that vertebrate mutators would be susceptible to cancer. I knew that adult fly and C. elegans somatic tissues did not continue to divide, and therefore could not get tumors. Mice were too expensive. In 1991, fish biochemist Gary Ostrander (now Dean at Hopkins), who was learning some molecular biological manipulations at my bench, suggested that I take a look at the 1984 NCI monograph on Fish as a cancer model. In that volume was Streisinger’s paper describing the mosaic eye phenotype as a way to detect somatic mutation. In an instant, I knew that this represented a way to detect the same type of somatic event that is seen in the second hit for any tumor suppressor gene, and that I had to do a screen for mutants with that phenotype. Several months later, after reading voraciously about zebrafish and talking with the incredibly supportive folks at University of Oregon (especially Charline Walker, George Streisinger’s first associate working with zebrafish, then postdoc Steve Johnson, who had been a Genetics graduate student at UW, and Monte Westerfield), I realized that parthenogenesis could be used to find mutators in zebrafish. I presented the idea in 1991 at one of their building-wide fish meetings. In the same monograph, I learned that tumors had been found in zebrafish. Larry Loeb was very helpful, in that he found an extra room for me to do my first experiments with zebrafish. Since that time, a variety of dedicated laboratory members and volunteers have helped us to establish the first zebrafish cancer laboratory. After years of dedication, Instructor Jessica has now found 12 genomic instability mutants that appear to show increased susceptibility to cancer.

What is your training philosophy?

This discussion will focus on training for graduate students and postdocs, and is oriented to individuals who plan to run a research laboratory. The most important determinants of success in any area are a strong sense of curiosity, self-motivation, and work-ethic. It is very helpful to be highly interactive. The successful investigator must have a common vocabulary that they will use to learn new things as they develop. They must also know how to recognize important biological problems and design well-controlled experiments to answer their chosen questions. The skill set required by all researchers includes ability to present one’s work in a well-organized and convincing manner in spoken and written forms. Grantsmanship is the packaging of one’s interests in a sponsor-specific manner, and to have some idea of the important criteria and potential pitfalls of grant-writing. Good laboratory skills include an ability to keep a well-organized notebook that completely describe well-designed experiments. Despite these common themes, every individual comes to the lab with a different set of motivations, abilities and knowledge. It is, therefore, important to customize training to the individual. Therefore, each trainee will be asked to study these requirements, and to identify specific goals in their training and criteria of success. To facilitate that training, question-asking and discussion are encouraged, as are collaboration development of independence, and training opportunities with high school students and undergraduates. We encourage individuals to think hard, work productively, encourage and inspire others, and to take their work more seriously than themselves.

What is required of graduate students for graduation?

Graduate students are expected to take a professional attitude as they strive towards a knowledge, skill, and attitude set that allows them to maximize the significance of their contributions to science. At least one major primary author publication, two collaborative publications, and a thesis will be required of each student. Primary commitment to graduate work is required.

How long will graduate school take?

A firm lab policy has been instituted that no student should spend more than 5 years to finish graduate school, except under extraordinary circumstances.

What is required for success in graduate school?

A commitment to excellence and contribution to science is primary. The successful graduate student will have a primary life commitment to graduate training. Essential success factors include excellent work ethic, attention to detail, record-keeping, intellectual rigor, communication with the mentor, initiative, interaction with other colleagues, and lab skills, as well as oral presentation and written skills.

What is expected of postdoctoral fellows?

Any successful scientist is driven by curiosity and a passion for excellence. Postdocs are expected to come with or to take on a project as their primary intellectual interest. This will involved submitting one or more grant applications to fund their time in fellowship. The successful postdoc should be able to publish at least two major and several collaborative papers during their tenure in the laboratory. At the end of their tenure, they should be able to carry some of their project with them into their career. At all times, fellows will be committed to the research, educational, and service missions of Penn State (primary, secondary, and tertiary to the fellow, respectively) and to follow professional codes of conduct. The collaborative nature of Cheng lab projects requires contributions from each lab member to a positive work environment.

How and when did you think of your histology screen?

At the Cold Spring Harbor Zebrafish at the end of April, 1996, the moment Mike Pack showed the histology of one of his gut mutants, I realized that unique mutants could be found directly by histology. I dropped everything to write an application to pursue a histological screen. The study section indicated an interest in the screen if I had a mutant. A surgery resident, Gladys Tsao-Wu, in the meantime, was interested in doing research in my lab. Luckily, Accelerated Executive Review of the application and evidence of our first two mutants that November netted the funding to find additional mutants. We are presently funded to perform a high-throughput screen. This has required creation of additional scanning and computer infrastructure, whose financial base is finally secured.

Explain your interest in Functional Genomics.

The sequencing of genomes was something that fascinated me for a long time. I also happen to love gadgets and have always been drawn to integrative solutions to important biological problems. To me this amounts to my definition of Functional Genomics: Combining Genetics, genomics, bioinformatics and proteomics to address biological function. I have worked successfully to foster cross-campus, coordinated, cross-genomic activities that take advantage of the strengths of different model organisms, genomics approaches, proteomics, and high throughput chemical screens, towards the goal of addressing important biological and medical problems. To date, I am pleased to report that three of my colleagues introduced to zebrafish are now committed: Robert Levenson (Pharmacology), Janet Robishaw (Weis Institute) and Glenn Gerhard (Weis Institute). The intent is to develop a Center of Excellence in Functional Genomics.

When did you become interested in cancer research?

As a medical student in 1977, I was given a slide show of what cancer looked like under the microscope. I was fascinated by the common features of cancer, and wanted from then to know how cancer cells got that way. My motivation comes from taking care of cancer patients as a medical student - I just hated that helpless feeling. Since that time, many friends have succumbed to cancer - it’s now personal. I became even more interested during my residency training in Anatomic Pathology, and went back to school to do a PhD during my residency so I would be better prepared to do interesting things in science.

How is it that you came to Penn State?

The Jake Gittlen Cancer Research Institute was hiring. The other institutions that interviewed me either didn’t have the space to accommodate a mutant screen in zebrafish or lacked understanding of our bold new initiative. Some institutional temerity was merited, since this was the beginning of a long period of 5-15% funding levels. At Penn State, I was promised space as long as I got the funding, and my creative boss, Dr. John Kreider, was game to the pursuit of my “crazy” idea. Anita Hopper suggested the critical connection with NSF program director DeLill Nasser. In short, a lot of hard work, volunteers, and two applications later, I had my start on a genomic instability screen. We have now found mutants for two screens, and are using functional genomic approaches to studying aspects of cancer, cell differentiation, and development in zebrafish.

Who are you willing to hire, and when?

Trainees desiring financial support will work on lab projects that are funded or aimed towards funding. Technicians are expected to function at a high level of contribution, but a minimum of two-year commitment is required. I am happy to help individuals with new ideas to develop them for pursuit in my lab, as long as they attract funding and are willing to contribute to a collaborative environment and commit to the betterment of the entire laboratory's missions. Scientifically qualified applicants who also happen to be chamber musicians are especially welcome.

I heard you are a musician. Tell us about it.

I have a deep love for music, especially chamber music. I view it as an ideal form of art. In chamber music, one has to take responsibility, play with love, be technically proficient, and be able to listen to others even while one is speaking musically. If everyone on earth behaved as one must in the best of chamber music, we would be living in a much better world. I have played the piano since I was 6 years old, and have seriously considered becoming a musician. However, I realized early on that the intellectual stimulation of science and the potential of making a unique contribution were stronger draws than my enjoyment of music. Thus, I decided to keep music as my primary "free time" activity. By asking always "What is the best possible interpretation of this piece?" and "What is the best technical way to execute each phrase?", and by performing, I have never stopped learning. Interestingly, it is useful to apply a similar approach to the technique and art of science as one takes to the technique and art of music.

What is MUSIC for JAKE, and are you playing again?

Warren Gittlen, who dedicates his life to raising money for cancer research, is always looking for new ways to raise money. Since I love chamber music, and wanted to enrich my community, I suggested a chamber music benefit concert. I had met Odin Rathnam, concertmaster of the Harrisburg Symphony Orchestra. He’s a most exuberant and passionate fellow, and I recognized immediately that he would be a delight to play with. Therefore, I suggested the idea to him, which he immediately agreed to. We have now partnered with a professional cellist three times. In 1996 with local cellist John Zurfluh, and in 1997 and 1999 with New York based, Avery Fisher Award winner Bion Tsang. The concerts were all near sell-outs at the historic Market Square Presbyterian Church in Harrisburg. We have performed a combination of violin showpieces, piano trios (piano, violin, cello), and cello pieces. I have decided, for the present, to focus on my laboratory, rather than play so much.

Why were you on the Board of Directors of WITF?

Past President Jane Coleman invited me as educational consultant. While on the board, I sought to build bridges between educational institutions such as Penn State and WITF, and to establish an endowment of significance. Current President and CEO Kathleen Pavelko, is one of the most articulate people I have ever met. I am proud to have worked with the other members of the Board of Directors on our mission statement, plans for a new facility, and future directions. It is my belief that our public media, if it continues to be driven by a passion for a globally-oriented vision of the future, understanding, and informing the public in a thoughtful way, will be a life-saving force in the United States and the world.

What is the Kienle Series?

The Hershey Medical Center is filled with talented people who not only perform medical care, research, and service to the community, but have interests in the arts. Given the financial and other stresses of academic life, I thought it important that we maintain our artistic outlets. Hence, Humanities Professor Ann Hawkins and I in 1999 founded the Kienle Humanities Series as a forum to host speakers about Medicine and Science and the Arts, as well as performances by professionals and by members of the Medical Center Community. The Knabe piano in Lecture Room A, donated by my family and rebuilt using funds raised from Humanities benefactor Dr. Kienle, many faculty members, and even students, is the centerpiece of the series. Past programs have included talks or concerts by violinist Odin Rathnam, Harrisburg Symphony Conductor Stuart Malina, WITF host Ellen Hughes, and pianist Robert Siemers. Our medical school is now acquiring a reputation around the country for its interest in the cultural interests of our students.